The intent of this proposal is to plan over a one-year period a prospective, open-label, randomized controlled trial of a currently available BCG vaccine to prevent primary M. tuberculosis infection. The vaccine will be administered to adults (students, researchers, health care workers, and humanitarians) from the USA visiting areas endemic for tuberculosis, especially those areas with high rates of MDR and XDR TB. Infection will be determined by blood interferon gamma release assay (IGRA) conversions following travel compared to pre-travel baseline testing. The practical goals of the study to be planned are both public health and scientific. The public health goal is to offer protection to the growing numbers of US visitors to high MDR/XDR risk sites where effective TB infection control interventions are rarely implemented. This is important because the morbidity and mortality of MDR/XDR TB, once it occurs, is much greater than that of drug susceptible TB, despite the best available treatment. Moreover, unlike latent infection with drug susceptible TB, there are no chemophrophylatic drug regimens proven effective in preventing progression or reactivation of latent infection. If BCG efficacy in preventing primary infection is rigorously tested, those data will inform forthcoming recommendations by ACET (CDC Advisory Committee for the Elimination of Tuberculosis) that travelers to high-risk sites consider BCG immunization in addition to more conventional TB infection control precautions, such as administrative controls, engineering controls, respiratory protection and conventional chemoprophylaxis following evidence of IGRA conversion. BCG is currently rarely used in the USA, although exposure to drug resistant tuberculosis is listed among the existing CDC BCG recommendations. The scientific goal of the study to be planned is to test the hypothesis that TB immunization prevents primary infection, as measured by IGRAs, rather than exclusively preventing extrapulmonary disease progression as has been classically taught. Until the availability of IGRA testing there was no way to test this hypothesis because the tuberculin skin test (TST) often becomes positive following BCG vaccination. However, several recent reports indicate fewer IGRA reactions among BCG vaccinated persons compared to comparably exposed unvaccinated persons. This study is further stimulated by the high cost and long duration of the clinical trials currently employed to test the efficacy of novel TB vaccines, which use tuberculosis disease as the primary outcome measure. In high-risk settings, there are ten to twenty new TB infections for every case that progresses to active disease among immunocompetent hosts. Using BCG as a proof-of-concept vaccine, convincing evidence of infection prevention could revolutionize both the goals of TB vaccine development and the approach to clinical trials of new candidate vaccines. The primary endpoint of the study will be the demonstration of a 50% reduction in IGRA conversion rate among vaccinated subjects compared to equally exposed unvaccinated subjects.